1. Field of the Invention
The present invention relates to the fields of chemistry and medicine. More specifically, the present invention relates to compounds and procedures useful in the treatment of cancer.
2. Description of the Related Art
It is thought that a single, universal cellular mechanism controls the regulation of the eukaryotic cell cycle process. See, e.g., Hartwell, L. H. et al., Science (1989), 246: 629-34. It is also known that when an abnormality arises in the control mechanism of the cell cycle, cancer or an immune disorder may occur. Accordingly, as is also known, antitumor agents and immune suppressors may be among the substances that regular the cell cycle. Thus, new eukaryotic cell cycle inhibitors are needed as antitumor and immune-enhancing compounds, and should be useful in the treatment of human cancer as chemotherapeutic, anti-tumor agents. See, e.g., Roberge, M. et al., Cancer Res. (1994), 54, 6115-21.
Recently, it has been reported that tryprostatins A and B (which are diketopiperazines consisting of proline and isoprenylated tryptophan residues), and five other structurally-related diketopiperazines, inhibited cell cycle progression in the M phase, see Cui, C. et al., J. Antibiotics (1996), 49, 527-33; Cui, C. et al. J. Antibiotics (1996), 49, 534-40, and that these compounds also affect the microtubule assembly, see Usui, T. et al. Biochem J. (1998) 333, 543-48; Kondon, M. et al. J. Antibiotics (1998) 51, 801-04. Furthermore, natural and synthetic compounds have been reported to inhibit mitosis, thus inhibit the eukaryotic cell cycle, by binding to the colchicine binding-site (CLC-site) on tubulin, which is a macromolecule that consists of two 50 kDa subunits (xcex1- and xcex2-tubulin) and is the major constituent of microtubules. See, e.g., Iwasaki, S., Med. Res. Rev. (1993) 13, 183-198; Hamel, E. Med. Res. Rev. (1996) 16, 207-31; Weisenberg, R. C. et al., Biochemistry (1969) 7, 4466-79. Microtubules are thought to be involved in several essential cell functions, such as axonal transport, cell motility and determination of cell morphology. Therefore, inhibitors of microtubule function may have broad biological activity, and be applicable to medicinal and agrochemical purposes. It is also possible that colchicine (CLC)-site ligands such as CLC, steganacin, see Kupchan, S. M. et al., J. Am. Chem. Soc. (1973) 95, 1335-36, podophyllotoxin, see Sackett, D. L., Pharmacol. Ther. (1993) 59, 163-228, and combretastatins, see Pettit, G. R. et al., J. Med. Chem. (1995) 38, 166-67, may prove to be valuable as eukaryotic cell cycle inhibitors and, thus, may be useful as chemotherapeutic agents.
Although diketopiperazine-type metabolites have been isolated from various fungi as mycotoxins, see Horak R. M. et al., J.C.S. Chem. Comm. (1981) 1265-67; Ali M. et al., Toxicology Letters, (1989) 48, 235-41, or as secondary metabolites, see Smedsgaard J. et al., J. Microbiol. Meth. (1996) 25, 5-17, little is known about the specific structure of the diketopiperazine-type metabolites and their antitumor activity, particularly in vivo. Furthermore, even though known antitumor substances isolated from microorganism metabolites (including anthracyclins and mitomycins that exhibit antitumor activity by binding to DNA) have been used as antitumor agents, see Microorganic Pharmaceutical Chemistry, revised 2nd edition, edited by Yoshio Ueno and Satoshi Ohmura, Nankohdo Publishing Co., (1986)), and even though anti-tumor substances having non-DNA binding operating mechanism have been isolated from microorganism metabolites, see Minoru Yoshida, M. Protein Nucleic Acid Enzymes (1993) 38, 1753; and Iwasaki, N., Chemistry and Living Organisms, (1994) 32, No. 3, 153, there is a particular need for new microorganism metabolite-derived compounds having animal cell-specific proliferation-inhibiting activity and high antitumor activity and selectivity. There is therefore a related need for substantially purified, and structurally and biologically characterized fungal diketopiperazine-type metabolites and fungal diketopiperazine-type metabolite-derivatives.
A compound, and any pharmaceutically acceptable salt or pro-drug ester thereof, suitable for use as an anti-tumor agent having the following generic structure: 
wherein:
R1, R2, R5, R7,and R8 are each separately selected from the group consisting of a hydrogen atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, substituted nitro, phenyl, and substituted phenyl groups, and
R3, R4, and R6 are each separately selected from the group consisting of a hydrogen atom, a halogen atom, and saturated C1-C12 alkyl, unsaturated C1-C12 alkenyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, and substituted nitro groups,
X1 and X2 are separately selected from the group consisting of an oxygen atom, and a sulfur atom, and
the dashed bond represents a bond selected from the group consisting of a carbon-carbon single bond and a carbon-carbon double bond.
In a preferred embodiment, the invention comprises, in substantially purified form, the compound herein named alternatively xe2x80x9c(xe2x88x92)-phenylahistin,xe2x80x9d xe2x80x9c(xe2x88x92)-NSCL-96F037,xe2x80x9d or xe2x80x9c(xe2x88x92)-PLH,xe2x80x9d which is a diketopiperazine composed of L-phenylalanine and isoprenylated dehydrohistidine. This compound has the following stereo-specific chemical structure: 
The invention also comprises a method of treating cancer comprising administering an effective tumor-growth-inhibiting amount of the compound, and any pharmaceutically acceptable salt or pro-drug ester of generic structure (I), and preferably, phenylahistin, and more preferably, (xe2x88x92)-phenylahistin, and pharmaceutically acceptable salt and pro-drug esters thereof. In preferred embodiments of the compound, salt, or pro-drug ester of the present invention, R3 and R4 are hydrogen, and each are involved in hydrogen bonds, and/or the dashed bond is a double bond.